Synthetic process and crystal form of condensed imidazopyridine derivatives

ABSTRACT

The present invention provides a process of a compound of the formula (I): 
                         
wherein R is heteroaryl or the like, ring A is a heteroalicyclic group or the like comprising reacting a compound of the formula (II):
 
                         
wherein Hal is halogen and the other symbols are the same as the above, in the presence of a sulfinic acid salt and further in the presence of an acid or a salt with an organic base, and a novel crystal form of 2-(3-isoxazolyl)-3,6,7,9-tetrahydroimidazo[4,5-d]pyrano[4,3-b]pyridine phosphate monohydrate.

This application is a U.S. national stage of PCT/JP01/02620 filed Mar.29, 2001.

TECHNICAL FIELD

The present invention relates to a novel synthetic process and a novelcrystal form of condensed imidazopyridine derivatives which are usefulfor pharmaceuticals.

BACKGROUND ART

Condensed imidazopyridine derivatives of the present invention arecompounds described in JP 1993/286973A and known to be useful aspsychotropic agents, antianxiety agents, anesthesia antagonistic agents,and cerebral function activators. In the above publication, a method forproducing the condensed imidazopyridine derivatives which are cyclizedby using N-methyl-2-pyrrolidone, biphenyl ether-biphenyl mixture etc. isdescribed. But it was very difficult to use this method for industrialproduction because it is necessary to react at 150° C. to 250° C.

This publication only describes that2-(3-isoxazolyl)-3,6,7,9-tetrahydroimidazo[4,5-d]pyrano[4,3-b]pyridineor salts thereof were obtained just as white crystals and does notindicate preferable crystal forms of phosphate or phosphate monohydrate.

Abstract of the 23rd Congress of Heterocyclic Chemistry, pp.97–99, 1992discloses a reaction for obtaining heterocyclic sulfonyl compounds fromits chloro compounds by using a sulfinic acid salt as a catalyst andthus obtained sulfonyl compounds are easily reacted by nucleophilicsubstitution of carbanions. But the publication does not suggest anaffection by addition of a catalyst such as an acid or a salt of anorganic base, specifically methanesulfonic acid.

DISCLOSURE OF INVENTION

The object of the present invention is to provide a novel syntheticprocess of condensed imidazopyridine derivatives, specifically2-(3-isoxazolyl)-3,6,7,9-tetrahydroimidazo[4,5-d]pyrano[4,3-b]pyridineor salts thereof and a novel crystal form of phosphate salt thereof.

The present invention provides

-   [1] A process for producing a compound of the formula (I):

-    wherein R is optionally substituted aryl or optionally substituted    heteroaryl and ring A is a 5- to 9-membered alicyclic group which    may contain one or more of O, S, SO, SO₂ and/or NR¹ (wherein R¹ is    hydrogen, alkyl, esterified carboxy, carbamoyl or acyl) and which    may be substituted with alkyl (hereinafter referred to as Compound    (I)), a pharmaceutical acceptable salt or solvate thereof comprising    reacting a compound of the formula (II):

-    wherein Hal is halogen and the other symbols are the same as the    above (hereinafter referred to as Compound (II)) in the presence of    a sulfinic acid salt,-   [2] The process as described in [1], wherein the reaction is carried    out in the presence of a) an acid or b) a salt with an organic base,-   [3] The process as described in [1] or [2] wherein R is 3-isoxazolyl    and ring A is

-   [4] The process as described in any one of [1] to [3] wherein the    sulfinic acid salt is a para-toluenesulfinic acid salt,-   [5] The process as described in any one of [2] to [4] wherein the    acid is methanesulfonic acid,-   [6] The process as described in any one of [2] to [5] wherein the    reaction temperature is 120° C. or lower,-   [7] A crystal of    2-(3-isoxazolyl)-3,6,7,9-tetrahydroimidazo[4,5-d]pyrano[4,3-b]pyridine    phosphate monohydrate of the formula (Ia):

-    (hereinafter referred to as Compound (Ia)), which has a powder    X-ray diffraction pattern having main peaks at diffraction angle    (2θ)=15.3, 17.8, 26.2, 11.6, 20.9, 25.7 and 27.9 (degree) and-   [8] The crystal as described in [7] which has a melting point of 162    to 175° C.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows powder X-ray diffraction chart of prism crystals.

FIG. 2 shows infrared absorption spectrum chart of prism crystals.

FIG. 3 shows powder X-ray diffraction chart of needle crystals.

FIG. 4 shows infrared absorption spectrum chart of needle crystals.

BEST MODE FOR CARRYING OUT THE INVENTION

In the present description, “halogen” includes fluorine, chlorine,bromine and iodine. Chlorine is preferable.

In the present specification, the term “aryl” includes phenyl, naphthyl,anthryl, indenyl, phenanthryl and the like.

The term “optionally substituted aryl” includes the above mentioned“aryl” which may have one or more of substituents selected from alkyl,hydroxy, alkoxy, aryloxy, acyloxy, carboxy, ester (e.g., alkoxycarbonyl,aralkoxycarbonyl etc.), cyano, amino, mono- or di-substituted amino,hydrazino, hydroxyamino, halogen, nitro, acyl, carbamoyl, thiocarbamoyl,carbamoyloxy, thiocarbamoyloxy, ureido, thioureido, sulfonamide, mono-or di-substituted sulfonamide, sulfonic acid, halogenoalkyl,hydroxyalkyl, alkoxyalkyl, acyloxyalkyl, nitroalkyl, aminoalkyl,acylaminoalkyl, cyanoalkyl, carboxyalkyl and the like. Preferableexamples are substituted or unsubstituted phenyl and the examples ofsubstituents for phenyl are methyl, methoxy, chloro and the like.

The term “heteroaryl” means a cyclic group containing one or more ofhetero atoms optionally selected from O, S and N in the ring and thecyclic group may condense with a carbocycle or another heterocycle. Theexamples of “heteroaryl” are 5- to 6-membered heteroaryl such aspyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, triazinyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl,thiazolyl, thiadiazolyl, furyl, thienyl etc., and condensed heteroarylsuch as indolyl, benzimidazolyl, indazolyl, indolizinyl, quinolyl,isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl,quinoxalinyl, pteridinyl, benzisoxazolyl, benzoxazolyl, oxadiazolyl,benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl,benzofuryl, benzothienyl, carbazolyl, phenazinyl etc.

As the substituents for “optionally substituted heteroaryl”, exemplifiedare alkyl, hydroxy, alkoxy, carboxy, ester (e.g., alkoxycarbonyl,aralkoxycarbonyl etc.), cyano, amino, mono- or di-substituted amino,hydrazino, hydroxyamino, halogen, nitro, acyl, carbamoyl, thiocarbamoyl,carbamoyloxy, thiocarbamoyloxy, ureido, thioureido, sulfonamide, mono-or di-substituted sulfonamide, sulfonic acid, halogenoalkyl,hydroxyalkyl, alkoxyalkyl, acyloxyalkyl, nitroalkyl, aminoalkyl,acylaminoalkyl, cyanoalkyl, carboxyalkyl and the like. Thesesubstituents may substitute at one or more of possible positions. Thesubstituents are preferably unsubstituted 5-membered heteroaryl, morepreferably unsubstituted thienyl, unsubstituted furyl, unsubstitutedisoxazolyl or unsubstituted pyridyl, and most preferably unsubstitutedisoxazolyl.

“A 5- to 9-membered alicyclic group which may contain one or more of O,S, SO, SO₂ and/or NR¹ wherein R¹ is hydrogen, alkyl, esterified carboxy,carbamoyl or acyl, and which may be substituted with alkyl” condenseswith the neighboring pyridine ring. The examples of alicyclic groups area carbocyclic group such as a cyclopenteno ring, a cyclohexeno ring, acyclohepteno ring, a cycloocteno ring, a cyclononeno ring etc., aheteroalicycle such as pyrrolidino, pyrrolino, imidazolidino,pyrazolidino, dihydrothiopheno, dihydrofurano, thiazolino,dihydropyranno, dihydrothiopyrano, piperidino, piperazino, morpholino,thiomorpholino, tetrahydropyridino, and tetrahydropyrimidino etc.Dihyclropyrano, dihydrothiopyrano or piperidino is preferable anddihydropyrano is especially preferable. These rings may be substitutedwith alkyl (e.g., one or two methyl, ethyl or the like).

The term “alkyl” includes a straight or branched alkyl having 1 to 10carbon atoms and a lower alkyl having 1 to 6 carbon atoms is preferable.For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl,2-metbylbutyl, n-hexyl, isohexyl, heptyl, isoheptyl, octyl, isooctyl,nonyl, decyl and the like are included.

The alkyl parts of “halogenoalkyl”, “hydroxyalkyl”, “alkoxyalkyl”,“acyloxyalkyl”, “nitroalkyl”, “aminoalkyl”, “acylaminoalkyl”,“cyanoalkyl” and “carboxyalkyl” are the same as the above “alkyl”.

The term “esterified carboxy” includes alkoxycarbonyl, aryloxycarbonyland aralkoxycarbonyl and the like. The examples are methoxycarbonyl,ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl and the like.

The term “acyl” includes an aliphatic acyl having 1 to 10 carbon atomsand an aromatic acyl. The examples are formyl, acetyl, propionyl,butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, acryloyl, propioloyl,methacryloyl, crotonoyl, cyclohexanecarbonyl, benzoyl, 4-nitrobenzoyl,4-tert-butylbenzoyl, benzenesulfonyl, toluenesulfonyl and the like.

The term “alkoxy” includes straight or branched alkoxy having 1 to 10carbon atoms and a lower alkoxy having 1 to 6 carbon atoms ispreferable. The examples are methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy,neopentyloxy, tert-pentyloxy, 2-methylbutoxy, n-hexyloxy, isohexyloxy,heptyloxy, isoheptyloxy, octyloxy, isooctyloxy, nonyloxy, decyloxy andthe like.

The alkoxy parts of “alkoxycarbonyl”, “alkoxyalkyl” and“aralkoxycarbonyl” are the same as the above “alkoxy”.

The aryl parts of “aryloxy”, “aryloxycarbonyl” and “aralkoxycarbonyl”are the same as the above “aryl”.

The acyl parts of “acyloxy”, “acylaminoalkyl” and “acyloxyalkyl” are thesame as the above “acyl”.

The substituents for “mono- or di-substituted amino” and “mono- ordi-substituted sulfonamide” include one or two of hydroxy, halogen,alkyl, alkenyl, acyl, aryl and the like.

“Compound (I)” includes any possible pharmaceutically acceptable salt ofeach compound. As the “pharmaceutically acceptable salt”, exemplifiedare salts with mineral acids such as hydrochloric acid, sulfuric acid,nitric acid, phosphoric acid, hydrofluoric acid, hydrobromic acid andthe like; salts with organic acids such as formic acid, acetic acid,tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid,succinic acid, methanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid and the like; salts with acidic amino acids suchas ornithine, aspartic acid, glutamic acid and the like. Phosphate ispreferable.

Compound (I) includes solvate thereof, wherein arbitrary numbers ofsuitable organic solvent or water molecules may coordinate to Compound(I). Hydrate is preferable and monohydrate is more preferable.

Compound (I) includes three kinds of tautomers and the above mentionedformula ) is just an example. Compound (I) includes other tautomers,i.e., Compound (I′) having double bonds at the 2–3, 3a–3b and 4–5position and Compound (I″) having double bonds at the 1–3b, 2–3 and 3a–4position of the following formulae.

Compound (I) can be obtained from Compound (II) by the followingreactions.

Compound (II) is reacted in a suitable solvent such asdimethylformamide, dimethylsulfoxide, N, N-dimethylimidazolidinone,N-methylpyrrolidone, dimethylacetoamide and Dautherm A in the presenceof a sulfinic acid salt for several tens minutes to several hours. Theexamples of a sulfinic acid salt are sodium para-toluenesulfinate,potassium para-toluenesulfinate, lithium para-toluenesulfinate, sodiummethanesulfinate, potassium methanesulfinate and lithiummethanesulfinate. The upper limit of the reaction temperature is around150° C., preferably around 145° C. and lower limit is around 90° C.,preferably around 100° C.

The above reaction is preferably subjected to further in the presence of“an acid” or “a salt with an organic base” in addition to the presenceof a sulfinic acid salt. The examples of “an acid” are methanesulfonicacid and para-toluenesulfinic acid. “A salt with an organic base” ispreferably a salt which has pKb 5 or lower, for example, hydrochlorideor hydrobromide with pyridine, N-methylmorpholine, N,N-dimethylpyridineor the like, hydrochloride, hydrobromide or methanesulfonate of Compound(I).

When the desired compounds are synthesized in the presence of “a) anacid or b) a salt with an organic base” and a sulfinic acid salt, thereaction may be conducted at about 130° C. or lower, preferably about120° C. or lower, and most preferably about 100° C. or lower. The lowerlimit for suitably conducting this reaction is about 90° C., preferablyabout 100° C.

The present reaction which is conducted in the presence of an acid or asalt with an organic base is very useful for inexpensive and simpleindustrial production of Compound (I) because of escaping the hightemperature reaction described in JP 1993/286973 A.

Compound (I) obtained by the present method can be turned into a freecompound, hydrochloride, methanesulfonate, maleate, phosphate or thelike by the conventional method. For example, methanesulfonate can beturned into a free compound by treating with sodium hydroxide. A freecompound can be crystallized as phosphate by treating with an aqueoussolution containing phosphoric acid (for example, 20% aqueousisopropanol).

Two kinds of crystal forms, i.e., prism crystals and needle crystalswere found as crystals of Compound (Ia), one of Compound (I) which canbe obtained by the above method. These crystals are distinguished bycharacteristic peaks of powder X-ray diffraction or absorption bands ofinfrared absorption spectrum.

For example, prism crystals can be obtained by the following method.

Firstly, a free compound, a salt or solvate of2-(3-isoxazolyl)-3,6,7,9-tetrahydroimidazo[4,5-d]pyrano[4,3-b]pyridineis obtained by the method described in JP 1993/2286973A or theabove-mentioned method. Thus obtained compound (for example, phosphate)is suspended in a diluted aqueous solution of phosphoric acid (about0.01 equivalent, preferably 0.05 equivalent). The suspension is stirredor allowed to stand under cooling or at room temperature for severalhours to recrystallize, and needle crystals of Compound (Ia) areobtained.

Free compound or hydrate of2-(3-isoxazolyl)-3,6,7,9-tetrahydroimidazo[4,5-d]pyrano[4,3-b]pyridinemay be crystallized as phosphate from an aqueous solvent (for example,aqueous methanol, aqueous ethanol, aqueous propanol, aqueous isopropanoland the like, preferably 20% aqueous isopropanol) containing phosphoricacid at the mole ratio of 1 to 2, preferably 1.2. Then, the obtainedcrystals may be recrystallized from a diluted aqueous solution ofphosphoric acid in the similar manner as the above.

Thus obtained needle crystals are suspended in a diluted aqueoussolution of phosphoric acid again and are kept with stirring or onstanding for about 1 to 3 days to obtain prism crystals. Prism crystalsof Compound (Ia) can be obtained when needle crystals are stirred withheating at about 30 to 100° C., preferably 60 to 100° C. for severaltens minutes to several hours. When recrystallization is carried out byadding seed crystals already prepared, the desired crystals are obtainedeffectively.

Prism crystals of Compound (Ia) are preferable because of high stabilityto heat and light as compared with needle crystals. Prism crystals haveanother advantage of good operation in synthetic processes because theyare easily separated from a solvent by filtration. Furthermore, prismcrystals are stable and high quality at ordinary temperature andatmospheric pressure because water molecules are contained in prismcrystal structure as crystal water by making hydrogen binding.

Melting point of prism crystals of Compound (Ia) is 162 to 175° C., moreclosely 167 to 170° C. The determination can be conducted according tothe melting point determination method in pharmacopoeia of Japan.

The present invention is further explained by the following Examples andExperiments, which are not intended to limit the scope of the presentinvention.

EXAMPLES

In the following Examples, X-ray diffraction of Compound (Ia) wasdetected under the following conditions.

-   X-ray diffraction conditions:-   Rigaku Corporation RAD-C, powder X-ray diffraction meter-   Target: Cu, Graphite Monochrometer, Tube voltage: 40 kV, Tube    current: 40 mA, Slit:-   DS=0.5, RS=0/3, SS=0.1, Scan Speed: 3°/min, Detector Scintilation    counter,-   Sample cell: small diameter, for small amount of samples (φ 5 mm)

Example 1 Synthesis of2-(3-isoxazolyl)-3,6,7,9-tetrahydroimidazo[4,5-d]pyrano[4,3-b]pyridine

1.25 g of Compound (II: Hal is Cl, R=3-isoxazolyl, ring A=dihydropyrano)was dissolved in 12 ml of DMF and 3.20 g of sodium para-toluenesulfinatewas added. The solution was heated to 110° C. and 0.86 g ofmethanesulfonic acid was added. Solution of 3.75 g of Compound (II) in12.5 ml of DMF was added dropwise over 1 hour at the same temperature.After the mixture was stirred for 1.5 hours at the same temperature andcooled, 40 ml of acetone was added to obtain a crude mixture salt(methanesulfonic acid salt and hydrochloride) of the titled compound.

Without drying, the obtained mixture salt was dissolved in 55.5 ml ofwater. 0.367 g of 96% sulfuric acid and 0.25 g of activated carbon wereadded and the mixture was stirred at 60° C. After cooling, activatedcarbon was filtered off and 18.5 g of 4.8% sodium hydroxide was added toneutralize. Crystallized crystals were filtered to obtain 3.99 g of freecompound dihydrate of the title compound (80% yield).

Example 2

Using a similar method of Example 1 except that the kind of sulfinicacid salt and existence or absence of acid, the desired compounds weresynthesized and the affection of a sulfinic acid salt and acid wasexamined. Synthesized compound was2-(3-isoxazolyl)-3,6,7,9-tetrahydroimidazo[4,5-d]pyrano[4,3-b]pyridinehydrochloride, which is described in JP 1993/286973 A. Number of moleequivalent in tables means the volume per 1 mole equivalent of Compound(II) and “1V” means 1 ml per 1 g of Compound (II).

TABLE 1 Reaction temperature Reaction Yield sulfinic acid salt acidsolvent (° C.) time (hr) (%) Lithium 1 mole — — DMSO 145 1 92.0para-toluene- equivalent (2V) sulfinate Lithium 0.5 mole   — — DMSO 1452 93.0 para-toluene- equivalent (2V) sulfinate Sodium 0.5 mole   — —DMSO 145 2 90.5 para-toluene- equivalent (2V) sulfinate Sodium 1 moleMethane- 0.5 mole NMP 94–97 1 90.4 para-toluene- equivalent sulfonicequivalent (4V) sulfinate acid Sodium 1 mole Methane- 0.5 mole NMP 94–972 94.0 para-toluene- equivalent sulfonic equivalent (4V) sulfinate acidNMP: N-methyl-2-pyrrolidone DMSO: dimethylsulfoxide

Reference Example 1 Synthesis of2-(3-isoxazolyl)-3,6,7,9-tetrahydroimidazo[4,5-d]pyrano[4,3-b]pyridine(free compound, dihydrate)

After 984 g of Compound (II: Hal=Cl, R=3-isoxazolyl, ringA=dihydropyrano) (3.53 mol) was added in a 5 L 4 necked flask equippedwith a stirrer, a thermometer and a nitrogen gas tube, 1.97 L ofN-methyl-2-pyrrolidone was poured therein to obtain a suspension. Thesuspension was reacted with stirring under mild nitrogen atmosphere for50 minutes at 190 to 210° C. (internal temperature) in oil bath of 200°C. After the reacted mixture was cooled to 40° C., 2 L of acetone wasadded to obtain the suspension. The obtained suspension was poured intoa 20 L 4 necked flask, 7.84 L of acetone was added and the mixture wascooled to 3° C. The precipitated crystals were filtered, washed twicewith 1.3 L of acetone and air-dried for 18 hours to obtain 879 g ofcrude crystals of2-(3-isoxazolyl)-3,6,7,9-tetrahydroimisazo[4,5-d]pyrano[4,3-b]pyridine(hydrochloride) (89.3%).

879 g of crude crystals were dissolved in 35.16 L of 20% aqueousisopropanol with heating and 505 ml of concentrated aqueous ammonia and295 g of activated carbon were added. After the solution was refluxedfor 20 minutes and activated carbon was filtered off, the filtrate waswashed with 6.7 L of warmed 20% aqueous isopropanol and 3.3 L ofisopropanol. The filtrate and wash liquid were mixed and concentratedunder reduced pressure to obtain 9.95 kg of a concentrated solution. Theobtained solution was cooled at 4° C. for 18 hours, precipitatedcrystals were filtered, washed twice with 1.8 L of ice-cooled 20%aqueous isopropanol and air-dried for 18 hours to obtain 764 g of thetitled compound (77.8%).

mp>300° C.

Elementary Analysis (C₁₂H₁₀N₄O₂.2H₂O)

Calcd.: C, 51.80; H, 5.07; N, 20.13; H₂O, 12.95%. Found: C, 51.85; H,5.10; N, 20.30; H₂O, 12.71%.

Reference Example 2 Preparation of Needle Crystals

To 764 g of the compound obtained in Reference Example 1 (free compound,dihydrate) in a 30 L reaction chamber, 26.75 L of 20% aqueousisopropanol was added and dissolved with stirring under heating at 80 to84° C. 76.4 g of activated carbon was added and the mixture was stirredfor 30 minutes at the same temperature. After the activated carbon wasfiltered off, the activated carbon was washed with 3.4 L of warmed 20%aqueous isopropanol. The filtrate and wash liquid were mixed andtransported to a 60 L crystallizer. The solution was warmed to 78° C. todissolve precipitated crystals, a solution of 389 g of 85% phosphoricacid (1.23 mol equivalent) in 389 ml of isopropanol was added and thedropping vessel was washed with 400 ml of isopropanol. Though needlecrystals were precipitated after one minute and the whole mixture wassolidified, it turned to be a suspension by stirring at high speed. Thusobtained suspension was cooled to 4° C. and allowed to stand for 18hours. After the suspension was took out from the crystallizer, it wasfiltered, washed twice with 4.6 L of isopropanol and air-dried at roomtemperature for 18 hours to obtain 946.5 g of Compound (Ia) as needlecrystals (96.2%).

mp 234–236° C.

Elementary Analysis (C₁₂H₁₀N₄O₂.H₃PO₄.H₂O)

Calcd.: C, 40.23; H, 4.22N, 15.63; P, 8.65; H₂O, 5.03%. Found: C, 40.39;H, 4.17N, 15.92; P, 8.53; H₂O, 4.10%.

powder X-ray diffraction: 12.4, 14.7, 17.4, 19.6, 21.4, 25.0, 27.0(degree)

IR: 3426, 3109, 1642, 1123, 998, 957 and 808 (cm⁻¹)

Example 3 Preparation of Prism Crystals

To 3119 g of needle crystals (8.705 mol) obtained in Reference Example 2in a 30 L enamel bat equipped with a stirrer, 18.71 L of distilled watercontaining 50.18 g of 85% phosphoric acid (0.05 mol equivalent) wasadded to obtain a suspension. Crystalline nucleus already prepared wasadded and stirred at room temperature (23 to 24° C.) for 43 hours. Theprecipitated crystals were filtered, washed twice with 1.5 L ofice-cooled distilled water and dried under reduced pressure at roomtemperature for 4 days to obtain 2902 g of Compound (Ia) as prismcrystals (93.1%).

mp 167 to 170° C. (formed fusion)

dp 242 to 252° C. (colored fusion)

Elementary Analysis (C₁₂H₁₀N₄O₂.H₃PO₄.H₂O)

Calcd.: C, 40.23; H, 4.22N, 15.63; P, 8.65; H₂O, 5.03%. Found: C, 40.25;H, 4.26N, 15.71; P, 8.64; H₂O, 5.16%.

powder X-ray diffraction: 11.6, 15.3, 17.8, 20.9, 25.7, 26.2 and 27.9(degree)

IR: 3264, 3104, 2533, 2085, 1648, 1119, 1089, 954 and 513 (cm⁻¹)

In the following Experiments, contents of Compound (I) were determinedby HPLC under the following conditions.

-   Device: WATERS 510, 481, 712 WISP, 741, FD20A or WATERS 510, 486,    712 WISP, 741, FD20A-   Column: YMC-packed column AM-302 S-5 120A ODS (4.6 mm φ×150 mm)-   Column temperature: room temperature-   Mobile phase: methanol/water/TFA=200/800/1 (v/v)-   Flow rate: 1.0 ml/min-   Wave length: 230 nm-   Concentration: 5–85 μg/ml-   Injection Volume: 15 μl

Purity of Compound (I) was observed by HPLC peaks detected by WATERS 991Photodiode Array Detector.

Experiment 1 Stability to Heat

Prism crystals and needle crystals of Compound (Ia) were used forsamples. About 25 mg of each crystal was put in a small glass containerwith polyethylene cap. Containers were capped, sealed with PARAFILM andkept at 40° C., relative humidity of 75% for 6 months. Prism crystalswere not observed appearance transition and needle crystals changed itscolor to pale yellow.

These results show prism crystals are more stable to heat compared withneedle crystals.

Experiment 2 Stability to Light

After samples were prepared in the same manner of Experiment 1 andsealed, they were kept under 1800 Lux exposure (16 hours exposure perday of a fluorescent lamp, 28800 Lux*hr/day) or under 10000 Lux exposure(continuous exposure of a fluorescent lamp, 240000 Lux*hr/day, averagetemperature 30±3° C.). As a standard reference sample, each of crystalswas put in a sealed container and kept at −20° C. The content ofcrystals were determined by the absolute calibration curve method usingHPLC under the above conditions. Results of observation of appearancetransition and remaining rate are shown below.

TABLE 2 Prism crystals Needle crystals appear- remaining appear-remaining ance rate (%) ance rate (%) 1800Lux 1 month − 100.0 ± or +98.6 2 months − 99.9 + 98.3 3 months − or ± 100.1 ++ 96.9 4 months ±100.1 ++ 97.0 10000Lux 1 week ± 99.5 ± or + 99.3 2 weeks ± or + 99.7 +98.0 3 weeks + 99.2 + or ++ 97.4

As shown the above, needle crystals changed the color to yellow andtheir remaining rate decreased after 3 months. Prism crystals scarcelychanged appearance and their remaining rate are more stable to light.

INDUSTRIAL APPLICABILITY

As shown in the above examples and experiments, the present process ofCompound (I) is useful for mass-production. Prism crystals of Compound(Ia) is exhibiting high stability and very useful for pharmaceutical rawmaterials.

1. A process for producing a compound of formula (I):

wherein R is optionally substituted aryl or optionally substitutedheteroaryl and ring A is a 5- to 9-membered alicylic group which maycontain one or more of O, S, SO, SO₂ and/or NR¹ wherein R¹ is hydrogen,alkyl, esterified carboxy, carbamoyl or acyl and which may besubstituted with alkyl, or a pharmaceutically acceptable salt or solvatethereof, comprising reacting a compound of formula (II):

wherein Hal is halogen and the other symbols have the same meaning asdefined above, in the presence of a sodium para-toluenesulfinate salt.2. The process as claimed in claim 1, wherein the reaction is carriedout in the presence of a) an acid or b) a salt of an organic base. 3.The process as claimed in claim 1 wherein R is 3-isoxazolyl and ring Ais


4. The process as claimed in claim 2 wherein the acid is methanesulfonicacid.
 5. The process as claimed in claim 2 wherein the reactiontemperature is 120° C. or lower.